The present invention relates to compounds that act to block calcium channels; methods of using the compounds to treat stroke, cerebral ischemia, pain, head trauma, asthma, amyotropic lateral sclerosis, or epilepsy; and to pharmaceutical compositions that contain the compounds of the present invention.
The entry of excessive amounts of calcium ions into neurons following an ischemic episode or other neuronal trauma has been well-documented. Uncontrolled high concentrations of calcium in neurons initiates a cascade of biochemical events that disrupts normal cellular processes. Among these events are the activation of proteases and lipases, breakdown of neuronal membranes, and the formation of free radicals, which may ultimately lead to cell death. Several types of calcium channels have been discovered and called the L, N, P, Q, R, and T types. Each type possesses distinct structural features, functional properties, and cellular/subcellular distributions. Type selective calcium channel blockers have been identified. For example, SNX-111 has been shown to be a selective N-type calcium channel blocker and has demonstrated activity in a number of models of ischemia and pain (Bowersox S. S. et al., Drug News and Perspective, 1994:7:261-268 and references cited therein). The compounds of the present invention are calcium channel blockers that can block N-type calcium channels and can be used to treat stroke, pain, cerebral ischemia, head trauma, asthma, amyotropic lateral sclerosis, and epilepsy.
The present invention provides compounds having the Formula I 
wherein
* denotes a first chiral center when R3 and R4 are different;
@ denotes a second chiral center;
R1 and R2 are independently hydrogen, C1-C8alkyl, C3-C7cycloalkyl, C1-C8substituted alkyl, C1-C6alkoxy, hydroxy, C3-C7cycloalkenyl, C3-C7substituted cycloalkenyl, C3-C7substituted cycloalkyl, xe2x80x94(CH2)n-aryl, xe2x80x94(CH2)n-substituted aryl, C2-C8alkenyl, C2-C8substituted alkenyl, xe2x80x94(CH2)n-heteroaryl, xe2x80x94(CH2)n-substituted heteroaryl, xe2x80x94(CH2)nxe2x80x94C3-C7cycloalkyl, xe2x80x94(CH2)nxe2x80x94C3-C7heterocycloalkyl, xe2x80x94(CH2)n-substituted C3-C7heterocycloalkyl, or R1 and R2 may be taken together to form a 5- to 7-membered ring which may contain a heteroatom, provided that R1 and R2 are not both hydrogen;
R3, R5, and R6 are independently hydrogen or C1-C8alkyl;
R4 is xe2x80x94(CH2)n-heteroaryl or xe2x80x94(CH2)n-substituted heteroaryl;
Y is xe2x80x94(CH2)nxe2x80x94, O(CH2)nxe2x80x94, xe2x80x94(CH2)nOxe2x80x94, xe2x80x94N(R7)(CH2)nxe2x80x94, xe2x80x94(CH2)nN(R7)xe2x80x94, xe2x80x94S(CH2)nxe2x80x94, xe2x80x94(CH2)nSxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, or xe2x80x94Cxe2x89xa1Cxe2x80x94;
R7 is hydrogen, methyl, or ethyl;
Z is aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C7cycloalkyl, substituted C3-C7cycloalkyl, C1-C8alkyl, xe2x80x94C3-C7heterocycloalkyl, or substituted C3-C7heterocycloalkyl;
X is OR8, NHR8, or NR8R9;
R8 and R9 are independently C1-C12alkyl, C1-C12substituted alkyl, xe2x80x94(CH2)nxe2x80x94C3-C8heterocycloalkyl, C3-C7cycloalkyl, substituted C3-C7cycloalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, or NR8R9 can together with the nitrogen atom form a ring having from 4 to 7 atoms;
each n is 0 to 5, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In a preferred embodiment of the compound of Formula I, R1 is 3-methylbutyl.
In another preferred embodiment of the compounds of Formula I, R3, R5, and R6 are hydrogen.
In another preferred embodiment of the compounds of Formula I, 
xe2x80x83xe2x80x94(CH2)npiperidine, or aminoethylpiperidine.
In another preferred embodiment of the compounds of Formula I, Y is xe2x80x94OCH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, or 
In another preferred embodiment of the compounds of Formula I, Z is phenyl.
In another preferred embodiment of the compounds of Formula I,
R1 is 3-methylbutyl;
R3, R5, and R6 are hydrogen;
R4 is xe2x80x94CH2pyridyl;
X is 
Y is xe2x80x94OCH2xe2x80x94; and
Z is phenyl.
In another preferred embodiment of the compounds of Formula I, R5 and R6 are hydrogen.
In another preferred embodiment of the compounds of Formula I, R2 is C1-C8alkyl, cyclohexyl, substituted cyclohexyl, xe2x80x94CH2-phenyl, or CH2-substituted phenyl.
In another preferred embodiment of the compounds of Formula I, X is 
In another preferred embodiment of the compounds of Formula I, R2 is C3-C7cycloalkenyl.
In another more preferred embodiment of the compounds of Formula I,
R1 is 3-methylbutyl;
R2 is C1-C8 alkyl, substituted cyclohexyl, cyclohexyl, cyclohexenyl, xe2x80x94CH2-phenyl, xe2x80x94CH2-substituted phenyl, xe2x80x94CH2-cyclohexyl, C1-C8alkenyl, xe2x80x94CH2-pyridyl;
R3, R5, and R6 are hydrogen;
R4 is xe2x80x94CH2pyridyl;
X is 
xe2x80x83xe2x80x94(CH2)npiperidine, or aminoethylpiperidine;
Y is xe2x80x94Oxe2x80x94CH2xe2x80x94; and
Z is phenyl.
In another more preferred embodiment of the compounds of Formula I, Y is xe2x80x94Oxe2x80x94CH2xe2x80x94 or 
Z is phenyl;
X is 
R3 and R5 are hydrogen;
R4 is xe2x80x94CH2pyridyl;
R1 is 3-methylbutyl; and
R2 is C1-C8alkyl, xe2x80x94(CH2)nsubstituted phenyl, or cyclohexyl.
In a most preferred embodiment of the present invention, the compounds are:
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(3-methyl-butylamino)-3-pyridin-4-yl-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohex-2-enylamino)-3-pyridin-4-yl-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(3-methyl-butylamino)-3-pyridin-3-yl-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohex-2-enylamino)-3-pyridin-3-yl-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(3-methyl-butylamino)-3-thiazol-4-yl-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohex-2-enylamino)-3-thiazol-4-yl-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-cyclohexylamino-3-thiazol-4-yl-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohexylmethyl-amino)-3-(1H-imidazol-4-yl)-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(1-methylethyl-amino)-3-(1H-imidazol-4-yl)-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohexyl-methyl-amino)-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(isobutyl-methyl-amino)-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[(3,3-dimethyl-butyl)-methyl-amino]-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohex-2-enyl-methyl-amino)-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[(4-dimethylamino-benzyl)-methyl-amino]-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[(4-methoxy-benzyl)-methyl-amino]-3-pyridin-4-yl-propionamide;
N-{-tert-Butylcarbamoyl-2-[4-(3,3-dimethyl-butyl)-phenyl]-ethyl}-2-(3-methyl-butylamino)-3-pyridin-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(3,3-dimethyl-butyl)-phenyl]-ethyl}-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-ethyl}-2-(3-methyl-butylamino)-3-pyridin-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-ethyl}-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-phenyl]-ethyl}-2-(3-methyl-butylamino)-3-pyridin-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-phenyl]-ethyl}-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzylamino-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(3-methyl-butylamino)-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzylamino-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-4-yl-propionamide;
N-[1-tert-Butylcarbamoyl-2-(4-phenethyl-phenyl)-ethyl]-2-(3-methyl-butylamino)-3-pyridin-4-yl-propionamide;
N-[1-tert-Butylcarbamoyl-2-(4-phenethyl-phenyl)-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-(2-piperidin-1-yl -ethylcarbamoyl)-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-4-yl-propionamide;
N-[1-(4-Benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-2-(3-methyl-butylamino)-3-pyridin-4-yl-propionamide;
N-[1-(4-Benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-2-(3-methyl-butylamino)-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohexyl-methyl-amino)-3-pyridin-3-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl ]-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-3-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(isobutyl-methyl-amino)-3-pyridin-3-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[(3,3-dimethyl-butyl)-methyl-amino]-3-pyridin-3-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohex-2-enyl-methyl-amino)-3-pyridin-3-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[(4-dimethylamino-benzyl)-methyl-amino]-3-pyridin-3-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[(4-methoxy-benzyl)-methyl-amino]-3-pyridin-3-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(3,3-dimethyl-butyl)-phenyl]-ethyl}-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-3-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-ethyl}-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-3-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-phenyl]-ethyl}-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-3-yl-propionamide;
N-[2-(4-Benzylamino-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-3-yl-propionamide;
N-[1-tert-Butylcarbamoyl-2-(4-phenethyl-phenyl)-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-3-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(3,3-dimethyl-butyl)-phenyl]-ethyl}-2-(3-methyl-butylamino)-3-pyridin-3-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-ethyl}-2-(3-methyl-butylamino)-3-pyridin-3-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-phenyl]-ethyl}-2-(3-methyl-butylamino)-3-pyridin-3-yl-propionamide;
N-[2-(4-Benzylamino-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(3-methyl-butylamino)-3-pyridin-3-yl-propionamide;
N-[1-tert-Butylcarbamoyl-2-(4-phenethyl-phenyl)-ethyl]-2-(3-methyl-butylamino)-3-pyridin-3-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-2-[(3-methyl-butyl)-amino]-3-pyridin-3-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-3-yl-propionamide;
N-[1-(4-Benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-2-[(3-methyl-butyl)-amino]-3-pyridin-3-yl-propionamide;
N-[1-(4-Benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-3-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohexyl-methyl-amino)-3-thiazol-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-thiazol-4-yl -propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(isobutyl-methyl-amino)-3-thiazol-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[(3,3-dimethyl-butyl)-methyl-amino]-3-thiazol-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohex-2-enyl-methyl-amino)-3-thiazol-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[(4-dimethylamino-benzyl)-methyl-amino]-3-thiazol-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[(4-methoxy-benzyl)-methyl-amino]-3-thiazol-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(3,3-dimethyl-butyl)-phenyl]-ethyl}-2-[methyl-(3-methyl-butyl)-amino]-3-thiazol-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(3,3-dimethyl-butyl)-phenyl]-ethyl}-2-[methyl-(3-methyl-butyl)-amino]-3-thiazol-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-ethyl}-2-[methyl-(3-methyl-butyl)-amino]-3-thiazol-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-ethyl}-2-[methyl-(3-methyl-butyl)-amino]-3-thiazol-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-phenyl]-ethyl}-2-[methyl-(3-methyl-butyl)-amino]-3-thiazol-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-phenyl]-ethyl}-2-[methyl-(3-methyl-butyl)-amino]-3-thiazol-4-yl-propionamide;
N-[1-tert-Butylcarbamoyl-2-(4-phenethyl-phenyl)-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-thiazol-4-yl-propionamide;
N-[1-tert-Butylcarbamoyl-2-(4-phenethyl-phenyl)-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-thiazol-4-yl-propionamide;
N-[1-tert-Butylcarbamoyl-2-(4-phenethyl-phenyl)-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-thiazol-4-yl-propionamide;
N-[1-tert-Butylcarbamoyl-2-(4-phenethyl-phenyl)-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-thiazol-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-2-(3-methyl-butylamino)-3-thiazol-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-thiazol-4-yl-propionamide;
N-[1-(4-Benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-2-(3-methyl-butylamino)-3-thiazol-4-yl-propionamide; or
N-[1-(4-Benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-thiazol-4-yl-propionamide.
Also provided is a pharmaceutical composition comprising a compound of Formula I.
Also provided is a method of blocking calcium channels, the method comprising administering to a patient in need of calcium channel blocking a therapeutically effective amount of a compound of Formula I to block calcium channels.
In a preferred embodiment of the method, the calcium channels are N-type calcium channels.
In another embodiment, the present invention provides a method of blocking N-type calcium channels, the method comprising administering to a patient in need of N-type calcium channel blocking a therapeutically effective amount of a compound of Formula I effective to block N-type calcium channels.
The invention also provides a method of treating stroke, the method comprising administering to a patient having or having had a stroke a therapeutically effective amount of a compound of Formula I.
The invention also provides a method of preventing a stroke, the method comprising administering to a patient at risk of having a stroke a therapeutically effective amount of a compound of Formula I.
The invention also provides a method of treating cerebral ischemia, the method comprising administering to a patient having cerebral ischemia a therapeutically effective amount of a compound of Formula I.
The invention also provides a method of treating head trauma, the method comprising administering to a patient having head trauma a therapeutically effective amount of a compound of Formula I.
The invention also provides a method of treating asthma, the method comprising administering to a patient having asthma a therapeutically effective amount of a compound of Formula I.
The invention also provides a method of treating amyotropic lateral sclerosis, the method comprising administering to a patient having treating amyotropic lateral sclerosis a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating epilepsy, the method comprising administering to a patient having epilepsy a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating pain, the method comprising administering to a patient having pain a therapeutically effective amount of a compound Formula I.
The present invention provides compounds having the Formula I 
wherein
* denotes a first chiral center when R3 and R4 are different;
@ denotes a second chiral center;
R1 and R2 are independently hydrogen, C1-C8alkyl, C3-C7cycloalkyl, C1-C8substituted alkyl, C1-C6alkoxy, hydroxy, C3-C7cycloalkenyl, C3-C7substituted cycloalkenyl, C3-C7substituted cycloalkyl, xe2x80x94(CH2)n-aryl, xe2x80x94(CH2)n-substituted aryl, C2-C8alkenyl, C2-C8substituted alkenyl, xe2x80x94(CH2)n-heteroaryl, xe2x80x94(CH2)n-substituted heteroaryl, xe2x80x94(CH2)nxe2x80x94C3-C7heterocycloalkyl, xe2x80x94(CH2)nxe2x80x94C3-C7cycloalkyl, xe2x80x94(CH2)n-substituted C3-C7heterocycloalkyl, or R1 and R2 may be taken together to form a 5 - to 7-membered ring which may contain a heteroatom, provided that R1 and R2 are not both hydrogen;
R3, R5, and R6 are independently hydrogen or C1-8alkyl;
R4 is xe2x80x94(CH2)n-heteroaryl or xe2x80x94(CH2)n-substituted heteroaryl;
Y is xe2x80x94(CH2)nxe2x80x94, xe2x80x94O(CH2)nxe2x80x94, xe2x80x94(CH2)nOxe2x80x94, xe2x80x94N(R7)(CH2)nxe2x80x94, xe2x80x94(CH2)nN(R7)xe2x80x94, xe2x80x94S(CH2)nxe2x80x94, xe2x80x94(CH2)nSxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, or xe2x80x94Cxe2x89xa1Cxe2x80x94;
R7 is hydrogen, methyl, or ethyl;
Z is aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C7cycloalkyl, substituted C3-C7cycloalkyl, C1-C8alkyl, C3-C7heterocycloalkyl, or substituted C3-C7heterocycloalkyl;
X is OR8, NHR8, or NR8R9;
R8 and R9 are independently C1-C12alkyl, C1-C12substituted alkyl, xe2x80x94(CH2)nxe2x80x94C3-C8heterocycloalkyl, C3-C7cycloalkyl, substituted C3-C7cycloalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, or NR8R9 can together with the nitrogen atom form a ring having from 4 to 7 atoms;
each n is 0 to 5, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
Two chiral centers that can have either R or S configurations are designated above in Formula I by the symbols xe2x80x9c*xe2x80x9d and xe2x80x9c@.xe2x80x9d It is intended that the present invention cover compounds having the S,S; R,R; S,R; or R,S configurations and mixtures thereof.
The term xe2x80x9calkylxe2x80x9d means a straight or branched chain hydrocarbon. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.
The term xe2x80x9calkoxyxe2x80x9d means an alkyl group attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
The term xe2x80x9chalogenxe2x80x9d includes chlorine, fluorine, bromine, and iodine.
The term xe2x80x9calkenylxe2x80x9d means a branched or straight chain hydrocarbon having one or more carbon-carbon double bond.
The term xe2x80x9carylxe2x80x9d means an aromatic hydrocarbon. Representative examples of aryl groups include phenyl and naphthyl.
The term xe2x80x9cheteroatomxe2x80x9d includes oxygen, nitrogen, and sulfur.
The term xe2x80x9cheteroarylxe2x80x9d means an aryl group wherein one or more carbon atom of the aromatic hydrocarbon has been replaced with a heteroatom. Examples of heteroaryl radicals include, but are not limited to, pyridyl, imidazolyl, pyrrolyl, thienyl, furyl, pyranyl, pyrimidinyl, pyridazinyl, indolyl, quinolyl, naphthyridinyl, and isoxazolyl.
The term xe2x80x9ccycloalkylxe2x80x9d means a cyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The symbol xe2x80x9cxe2x80x94xe2x80x9d means a bond.
The term xe2x80x9cpatientxe2x80x9d means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.
The term xe2x80x9csubstitutedxe2x80x9d means that the base organic radical has one or more substituents. For example, substituted cyclohexyl means a cyclohexyl radical that has one or more substituents. Substituents include, but are not limited to, halogen, C1-C8alkyl, xe2x80x94CN, CF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHC1-C8alkyl, xe2x80x94N(C1-C8alkyl)2, xe2x80x94OC1-C8alkyl, and xe2x80x94OH. Particularly preferred substituents include, but are not limited to, tert-butyl, methyl, chlorine, fluorine, bromine, xe2x80x94OCH3, xe2x80x94OCH2CH3, xe2x80x94OH, and xe2x80x94N(CH3)2.
The term xe2x80x9ccycloalkenylxe2x80x9d means a cycloalkyl group having at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopentene, cyclobutene, and cyclohexene.
The term xe2x80x9cheterocycloalkylxe2x80x9d means a cycloalkyl group wherein one or more carbon atom is replaced with a heteroatom. Examples of heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, and piperazinyl.
Those skilled in the art are easily able to identify patients having or having had a stroke or at risk of having a stroke, cerebral ischemia, head trauma, asthma, amyotropic lateral sclerosis, or epilepsy. For example, patients who are at risk of having a stroke include, but is not limited to, patients having hypertension or undergoing major surgery.
A therapeutically effective amount is an amount of a compound of Formula I, that when administered to a patient, ameliorates a symptom of the disease.
The compounds of the present invention can be administered to a patient either alone or a part of a pharmaceutical composition. The compositions can be administered to patients either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The term xe2x80x9cpharmaceutically acceptable salts, esters, amides, and prodrugsxe2x80x9d as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term xe2x80x9csaltsxe2x80x9d refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, Berge S. M. et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.)
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C1-C6alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7cycloalkyl esters as well as arylalkyl esters such as, but not limited to, benzyl. C1-C4alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6alkyl amines and secondary C1-C6dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycloalkyl group containing one nitrogen atom. Amides derived from ammonia, C1-C3alkyl primary amines, and C1-C2dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, xe2x80x9cPro-drugs as Novel Delivery Systems,xe2x80x9d Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
In addition, the compounds of the present invention can exist in unsolvated, as well as solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The compounds of the present invention can exist in different stereoisomeric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisomeric forms of the compounds, as well as mixtures thereof including racemic mixtures, form part of this invention.
The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art.
In addition, it is intended that the present invention cover compounds made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as through metabolism.
The examples presented below are intended to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims, in any way.
The following abbreviations are used throughout this application: